Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1)

Abstract

A mathematical model capable of accurately characterizing intracellular disposition of ADCs is essential for a priori predicting unconjugated drug concentrations inside the tumor. Towards this goal, the objectives of this manuscript were to: (1) evolve previously published cellular disposition model of ADC with more intracellular details to characterize the disposition of T-DM1 in different HER2 expressing cell lines, (2) integrate the improved cellular model with the ADC tumor disposition model to a priori predict DM1 concentrations in a preclinical tumor model, and (3) identify prominent pathways and sensitive parameters associated with intracellular activation of ADCs. The cellular disposition model was augmented by incorporating intracellular ADC degradation and passive diffusion of unconjugated drug across tumor cells. Different biomeasures and chemomeasures for T-DM1, quantified in the companion manuscript, were incorporated into the modified model of ADC to characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When the cellular model was integrated with the tumor disposition model, the model was able to a priori predict tumor DM1 concentrations in xenograft mice. Pathway analysis suggested different contribution of antigen-mediated and passive diffusion pathways for intracellular unconjugated drug exposure between in vitro and in vivo systems. Global and local sensitivity analyses revealed that non-specific deconjugation and passive diffusion of the drug across tumor cell membrane are key parameters for drug exposure inside a cell. Finally, a systems pharmacokinetic model for intracellular processing of ADCs has been proposed to highlight our current understanding about the determinants of ADC activation inside a cell.

Keywords: T-DM1; antibody-drug conjugate; cellular pharmacokinetics; global sensitivity analysis; mechanistic model; model-based drug development; tumor disposition; tumor pharmacokinetics.

Fig. 1

Schematics of PK models used to characterize the disposition of T-DM1. a Cellular disposition model for T-DM1 characterizing the intracellular processing and release of DM1 catabolites in the intracellular and extracellular space. b A combined PK model consisting of two integrated two-compartment models characterizing the disposition of T-DM1 and released DM1 catabolites simultaneously. c Full multiscale mechanistic tumor PK model capable of predicting tumor concentrations of released DM1 catabolites based on plasma T-DM1 PK

Fig. 2

Observed and model generated profiles of total, conjugated, and unconjugated maytansinoids inside the cells, and unconjugated and total DM1 in the media, after treating BT-474EEI, SK-BR3, and MCF-7/neoHER2 cells with DM1 (10)

Fig. 3

Observed and model generated plasma PK profiles of total trastuzumab and T-DM1, after a 2 mg/kg and b 3 mg/kg dose of T-DM1 in non-tumor-bearing mice. c Observed and model generated plasma PK profile of T-DM1 after 0.3, 3, and 15 mg/kg intravenous dose of T-DM1 in tumor-bearing mice. d Observed and model generated plasma PK profile of DM1 after intravenous DM1 administration in rats

Fig. 4

Observed and a priori model predicted profiles of a total maytansinoids and b unconjugated maytansinoids in the tumor, and c total plasma maytansinoids, obtained after IV administration of 300 μg/kg [H]³DM1-based dose of T-[H]³DM1 in BT-474EEI tumor-bearing mice

Fig. 5

a Local sensitivity of the improved cellular disposition model with respect to intracellular unconjugated (tubulin) bound drug as an output, b pathway analysis of in vitro cellular disposition model for assessing relative importance of antigen-mediated and diffusion pathways of intracellular drug delivery, and c pathway analysis of in vivo tumor disposition model for assessing relative importance of antigen-mediated and diffusion pathways of intracellular drug delivery

Fig. 6

Results from global sensitivity analysis. Sobol analysis on: a in vitro cellular disposition model of ADC, b in vivo tumor disposition model of ADC using intra-tumoral kinetic parameters, and c in vivo tumor disposition model of ADC using systemic PK parameters. PRCC analysis on: d in vitro cellular disposition model of ADC, e in vivo tumor disposition model of ADC using intra-tumoral kinetic parameters, and f in vivo tumor disposition model of ADC using systemic PK parameters

Fig. 7

Schematics of a proposed systems pharmacokinetic model for intracellular processing of ADCs, which highlights our current understanding about the determinants responsible for ADC activation in a cell